Vitamin E deficiency in humans results in a progressive, debilitating, dysfunction of the peripheral nervous system. From measurements of the tocopherol (vitamin E) content of plasma, red blood cells, and of a needle biopsy of the adipose tissue, we have documented that patients with lipid malabsorption syndromes (abetalipoproteinemia (ABL), cholestatic liver disease, short bowel syndrome, etc.), before supplementation with vitamin E, have strikingly low adipose tissue tocopherol levels. The lower this value, the more advanced the neurologic disability is likely to be; administration of vitamin E sufficient to raise adipose tissue tocopherol levels can halt the progression of the neurologic disease, and in some cases can partially reverse the abnormalities. Patients with "Familial Vitamin E Deficiency with Neurologic Abnormalities" have normal lipid absorption, lipoprotein patterns and liver function, yet they require supplemental vitamin E (800 IU/day) in order to maintain normal plasma tocopherol levels. We plan to follow these and other patients at risk for vitamin E deficiency, to monitor vitamin E status and to document peripheral nervous system function. The tocopherol content of sural nerve and liver will be measured, when these tissues are biopsied for studies of abnormal pathology. Studies are planned both in vivo and in vitro to define the mechanisms involved in tocopherol absorption and transport in the plasma, its transfer to tissues and its intracellular distribution. Several aspects of tocopherol absorption from the intestine are under investigation--a) absorption of water-miscible forms of vitamin E by patients with cholestasis, b) uptake of tocopherol by intestinal cells, and c) measurement of the absorption of vitamin E using deuterated tocopherol. (Studies with deuterated tocopherol will also provide measurement of the kinetics of tocopherol pool size and turnover, along with providing labeled lipoproteins and cells for biophysical studies.) Studies on the transport of tocopherol in the plasma will investigate the roles of normal lipoproteins (chylomicrons, VLDL, LDL and HDL) and abnormal lipoproteins, including LpX from cholestatic patients. Studies on the transfer of tocopherol to cells have demonstrated that both the LDL receptor mechanism and the enzyme, lipoprotein lipase, function to deliver tocopherol to cells; further investigations on lipase (different sources, inhibitors--bile salts and antibodies) are planned, as well as studies on the ability of known lipid transfer proteins to move tocopherol between lipoproteins, or between lipoproteins and cells. Finally, studies are in progress to delineate the intracellular location of tocopherol in adipocytes from normal human adipose tissue.